Human and experimental animal studies have demonstrated that repeated exposure to stressful stimuli may damage neurons or increase the probability of their damage by future neurological insults. Whether stress potentiates the neurotoxic effects of the psychostimulant methamphetamine (METH) on dopamine and serotonin neurons is unknown. The goal of this proposal is to determine whether repeated exposure to Stress enhances the neurotoxicity of METH and to elucidate the mechanisms of that interaction. The immediate changes in transmitter release and long-term transmitter depletions will be measured following neurotoxic treatment with METH in unstressed rats and in rats exposed to chronic, unpredictable stress. It is hypothesized that stress will exacerbate the METH-induced increase in transmitter release and long- term depletions in tissue content. To further identify the mechanisms contributing to the neurotransmitter depletions, several studies will investigate whether alterations in glutamate, intracellular calcium and/or the neurotrophic factor, brain-derived neurotrophic factor (BDNF), are involved. The response of BDNF to METH alone and in combination with repeated stress will be characterized in several brain regions. Based on previous research, it is expected that chronic stress will augment the long-term decreases in BDNF levels following METH treatment and that injecting BDNF into susceptible brain regions will block the METH-induced neurotransmitter depletions. The ability of BDNF to prevent some of the neurotoxin effects of METH would support the role of neurotrophins as potential therapeutic agents for stress-related illnesses.